Addiction to cocaine and methamphetamine, highly addictive psychostimulants, is associated with substantial neuropsychiatric morbidity, as well as enhancing transmission of HIV-1, hepatitis B and C, and drug resistant tuberculosis, and thus causing massive public health costs. Presently, there are no FDA approved treatments for psychostimulant abuse. A growing body of evidence has shown that ? opioid (KOP) receptors are involved in the modulation of some of the abuse related effects of psychostimulants. Notably, repeated or chronic psychostimulant administration results in a prolonged upregulation of the KOP receptor/ dynorphin system. The KOP receptor/ dynorphin system is a major part of the brain's counter-regulatory esponse to enhanced dopaminergic acitivity, which is a major initial event underlying psychostimulant-induced reinforcement and abuse potential. Kappa opioid receptors have also been implicated in the actions of Salvia divinorum, a hallucinogenic mint plant that is currently unscheduled and readily available to the public over the Internet. Due to the recent increase in the popularity of Salvia divinorum among both European and American teens, the DEA has recently placed it on the list of drugs to watch. It is predictable that its misuse will increase rapidly. The central hypothesis of this proposal is that structural modification of salvinorin A will lead to identification of novel kappa opioid receptor ligands with the potential to treat drug dependence and its relapse. The long-term goal of this research is to develop neoclerodane-derived KOP ligands with pharmacotherapeutic potential in psychostimulant addiction and relapse, as well as neuropsychiatric disorders (including anxiety, depression and stress-related disorders such as PTSD). The specific aims of this proposal are (1) optimize the activity of neoclerodanes at KOP receptors;(2) identify novel naturally occurring neoclerodanes with KOP activity;and (3) determine the biological activity of compounds in vivo. The proposed research is innovative because neoclerodanes are a unique class of opioid receptor ligands. The design, synthesis, isolation, and evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with KOP receptors. This information is expected to facilitate the identification of clinically useful KOP- targeted drugs for the treatment of drug abuse and major neuropsychiatric disorders. PUBLIC HEALTH RELEVANCE: Stimulant dependence is a chronic relapsing disease that results from the prolonged effects of drugs on the brain. At present, there are no FDA-approved therapeutic agents available for the treatment of stimulant abuse or for the prevention of its relapse. This project seeks develop neoclerodane-derived ? opioid (KOP) receptor ligands with pharmacotherapeutic potential in psychostimulant addiction and relapse, as well as neuropsychiatric disorders (including anxiety, depression and stress-related disorders such as PTSD). The design, synthesis, isolation, and evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with KOP receptors. This information is expected to facilitate the identification of clinically useful KOP-targeted drugs for the treatment of drug abuse and other neuropsychiatric disorders.